John Y. Killen, M.D., Director, DAIDS
The AIDS Subcommittee of the National Advisory Allergy and Infectious Diseases Council and the AIDS Research Advisory Committee (ARAC) met jointly on September 26, 2000 at the Natcher Building on the National Institutes of Health (NIH) campus in Bethesda, Maryland. Dr. Killen chaired the meeting, which was open to the public.
Report from the Director – Dr. Killen
After reviewing staff changes and NIAID's budget, Dr. Killen discussed a number of significant scientific advances and highlights from NIAID-funded research in FY 2000. These included the following:
- The importance of viral load in heterosexual transmission of HIV based.
- The completion of the first HIV vaccine trial in Uganda.
- The safety of a novel microbicide, BufferGel, demonstrated in early phase I studies.
- Documentation of HIV transmission throughout breast-feeding.
- The creation of stabilized forms of recombinant HIV envelope proteins for possible use in an HIV vaccine.
- The usefulness of genotypic antiretroviral resistance testing (GART).
- Improved understanding of the mechanisms, timing and location of the emergence of HIV.
- Further elucidation of the association between sexually transmitted diseases (STDs) and an increased risk of acquiring HIV infection.
- The identification of a novel protein (DC-SIGN), which appears to play an important role in HIV infection of dendritic cells.
- The correlation between the level of HIV in the genital tract and viral load.
Dr. Killen reviewed awards that had been made since the last meeting and described the status of several initiatives.
- The RFA for renewal of the Pediatric ACTG was released on September 15. Pre-applications are due in October 2000, applications due in March 2001 and peer review will likely take place in September 2001. An award is expected in March 2002.
- Dr. Killen reviewed ongoing efforts to assess the feasibility of a "when to start therapy" clinical trial, which included a recent workshop. DAIDS will continue to actively pursue research to address this important question.
- The HIV Vaccine Trial Network (HVTN) and HIV Prevention Trials Network (HPTN) are fully funded, greatly increasing NIAID's global capacity to support HIV vaccine and prevention trials.
Inter-Institute AIDS Drug Development Initiative – Dr. Kagan
In the 1980s, NIAID and NCI divided responsibilities in AIDS research particularly with regard to screening compounds and drug development. NCI focused on antiretroviral drugs, building on its large chemical library and capacity to synthesize and test compounds, while NIAID focused on opportunistic infections (OIs) and large-scale clinical trials.
In early 1999, NIAID proposed that the two institutes work more closely together and expand their drug development program to facilitate collaboration with academia and industry. The resulting Inter-Institute AIDS Drug Development Initiative brings NIH's AIDS therapeutic discovery and development resources together in a comprehensive program, regardless of the institute. This revised approach is particularly important for high-risk research, for smaller companies that do not have the resources to develop interesting compounds, and perhaps for pursuing compounds that large pharmaceutical companies may own but not have an interest in developing. Dr. Steve Turk chairs the committee that oversees this initiative, which will be announced later in the year in major scientific journals.
Concept Review: Drug Development for Opportunistic Infections – Dr. Lambros
The incidence of OIs has declined dramatically in the U.S. due to highly effective antiretroviral therapy. However future trends are uncertain. The development of resistance to antiretroviral (ART) may lead to a resurgence of OIs in the United States, and OIs remain a significant problem in developing countries that do not have access to ART. These contracts are therefore, still necessary as it assists investigators that want to test new therapeutic concepts or approaches. These contracts have a great deal of flexibility in responding to changes in the incidence of specific OIs, and are not locked into the listed AIDS-defining OIs.
For example, research on microsporida is being phased out, and success in the area of mycobacterium avium is leading to a downsizing of that program. Contracts on Pneumocystis carinii, Cryptococcus neoformans, and Cryptosporidium parvum will be held at the same levels, and a new program on hepatitis C will be developed. Work on tuberculosis continues under a separate program.
The Committee unanimously approved the concept for this initiative.
Prevention Research: An Overview
HIV Biomedical and Behavioral Prevention Research at NIH – Dr. Auerbach
Non-vaccine research remains essential because a vaccine will likely be less than 100 percent effective, it is years away from reality and it is unclear how an HIV vaccine would be utilized in developed countries. Most importantly, the two approaches are not mutually exclusive and need to be pursued simultaneously.
Prevention research should include the traditional prevention of acquisition of HIV infection as well as the secondary consequences of HIV and AIDS - physical, psychological, and social.
Trans-NIH prevention expenditures in FY 2000 were $755, or 37.6 percent of the total AIDS research budget. Vaccine research was $239 million (11.8 percent) and non-vaccine prevention activity was $516 million (25.7 percent) of that total budget.
NIAID Prevention Research – Dr. Johnston
Most of NIAID's prevention research activity is focused on discovery, preclinical and clinical work associated with HIV, STDs and OIs that may contribute to the spread of HIV. NIAID's focus is on the biomedical, and for clinical studies, on HIV endpoints rather than behavior change or drug use.
Most non-vaccine prevention projects are investigator-initiated. Fundamental research focuses on pathogen interaction with target cells and mucosal surfaces and is geared toward developing targets that are amenable to biomedical prevention intervention. Preclinical work ranges from developing assays to something akin to product development. There are also a small number of contracts that support the safety evaluation of microbicides in animal models. The major clinical program is the HIV Prevention Trials Network, although other NIAID-funded clinical trials networks conduct some prevention research.
HIV Prevention Trials Network (HPTN) Overview – Dr. Cates
The HPTN was fully established in July 2000 when awards were made to the clinical sites in the United States (10 sites) and twelve other nations (16 sites).
Family Health International is the operations and administrative center of the network; the Fred Hutchinson Center at the University of Washington is the statistical and data management center and Johns Hopkins University maintains the Central Laboratory.
The HPTN has six working groups focusing on perinatal transmission, microbicides, behavioral interventions, sexually transmitted diseases (STD) control, antiretroviral therapy for prevention, and substance use. A seventh working group coordinates community participation.
Perinatal Transmission – Dr. Jackson
Ever since ACTG 076 demonstrated that use of AZT could reduce the rate of perinatal transmission of HIV by two-thirds, the rates have been declining wherever the intervention is used. Further research and more powerful therapies have brought transmission down in the U.S. from a peak of 1,500 a year to less than 300 in 1999, and most of those infections were in infants of women who did not know that they were infected with HIV. For those HIV-infected pregnant women receiving therapy, the prevention of perinatal transmission "is approaching 100 percent efficacy." However, the number of cases in the developing world continues to rise.
The HIVNET 012 trial demonstrated that a short course of nevirapine is another effective way to reduce perinatal transmission, and it is simpler, easier to administer and less expensive that AZT. While this regimen may have worldwide implications to reducing mother to infant transmission of HIV, researchers have raised the issue that nevirapine has a half-life of 60 hours, and when used as a monotherapy, mutation resistance can quickly appear in the virus. Most HIV-infected individuals who develop this resistance revert to wildtype virus within a few months. If neither the mother nor child (who may become infected with mutant virus) have access to ART in the future, then the matter may be of little consequence, but such mutations may inhibit or preclude use of ART at some future time, should it become more affordable.
Research in the HPTN continues to evaluate cost-effective strategies for reducing HIV perinatal transmission globally, including research on the impact of breast-feeding and whether reasonable alternatives exist to limit mother to infant transmission through breast milk.
Microbicides – Dr. Hillier
Microbicides are topical agents used vaginally or rectally to prevent sexually transmitted infections, including HIV. They are seen as a complement to, not a substitute for condom use. Principle challenges in developing marketable microbicidal products include:
- A multidisciplinary approach involving one or more active ingredients, that may use a variety of different killing, neutralizing, and barrier approaches, combined with a carrier, which also may be highly variable
- Sensitivities of vaginal and rectal environments where the products will be used
- The need for both contraceptive and non-contraceptive options
- Dissatisfaction with the rabbit model, which likely necessitates use of a monkey/SIV or SHIV model
- The size and complexity of trials necessary to test the efficacy of microbicide products
- Public acceptance of the use, feel, and taste of the product both within and across cultural lines probably calls for a spectrum of product formulations
- Reluctance of major pharmaceutical companies to develop such a product because they do not believe the potential market to be attractive enough
- Safety, liability, and political sensitivity surrounding sexual issues all contribute to further inhibit industry interest in developing such a product.
The pipeline of compounds under investigation has improved markedly over the last five years and now numbers in the dozens. Most are in preclinical or phase I/II trials. Only 4 phase III trials have been completed and all involved nonoxynol-9 (N-9), approved for use as a spermicide. The anti-HIV effect of N-9 seen in vitro has not been proven in vivo and under at least some circumstances of use, N-9 irritates epithelial tissue and increases the risk of acquiring HIV.
The HPTN is trying to speed up development of microbicides by involving higher risk women in phase I/II clinical trials and by involving sexual partners in early phases of trials to get a better sense of product acceptance. The HPTN recognizes that acceptance may vary, not only between cultures but also between age groups within a single culture.
Proof of concept is crucial in attracting the participation of large pharmaceutical companies that have the depth of resources to commercially develop and market viable products.
Concept Review: Integrated Preclinical/Clinical Program in Topical Microbicides (IPCP) – Dr. Black
This initiative will support critical path development of specific microbicide concepts and strategies, encourage the translation of on-going HIV specific drug discovery and development to microbicide approaches and require a strong commitment and collaboration with industry. The Division of AIDS anticipates awarding 7-9 project grants. Preclinical projects would have a maximum duration of up to four years and projects proposing a pilot clinical study would have a maximum during of up to five years. The committee voted unanimously to approve the concept for this initiative.
Sexually Transmitted Diseases –Dr. Quinn
The priorities and key questions that will be addressed by the HPTN working group on STDs include:
- Impact of STD control in populations with high and low incidence of HIV
- Impact of HIV viral load on shedding and transmission of virus
- Roles that male circumcision and penile hygiene play in HIV and STD transmission
- Impact of intense and repeated counseling on behavior
Dr. Quinn described in detail five HPTN protocols currently being conducted or planned in the US and overseas.
ART as a Tool of Prevention – Dr. Cohen
The hypothesis, based upon work with tuberculosis, and in part reinforced by data on HIV discordant couples, is that lower viral load reduces the likelihood of HIV transmission. The HPTN ART Working Group is proposing to examine the impact of antiretroviral therapy as a means of prevention among discordant couples, in primary infection, as pre-exposure prophylaxis, and as post-exposure prophylaxis.
The choice of treatment regimen, the logistics of implementing these studies, and sustainability are all issues that still need to be addressed.
During discussion, the point was raised that the availability of therapy could potentially increase voluntary testing and counseling, providing another opportunity to intervene with prevention messages and resulting in a synergistic effect between the effective ART and increased prevention measures.
Behavioral Interventions – Dr. Cates
Most behavioral research is nested within each of the other working groups of the HPTN. The key priority is community level interventions to try and change social norms, particularly those affecting the role and status of young women in developing nations. Peer networking and leadership is a crucial element in making these programs effective and sustainable. The behavioral studies draw on the expertise from across various Institutes of the NIH and academic and international collaborators.
The Behavioral Interventions Working Group has identified a number of worthy projects and will have to critically evaluate the capacity of sites in the network and set priorities within the next several months.
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